rs1341863

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001103.4(ACTN2):c.378C>T(p.Asn126Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,611,842 control chromosomes in the GnomAD database, including 776,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 66858 hom., cov: 33)

Exomes 𝑓: 0.99 ( 709267 hom. )

Consequence

ACTN2
NM_001103.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.102

Publications

22 publications found

Variant links:

Genes affected

ACTN2 (HGNC:164): (actinin alpha 2) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACTN2 Gene-Disease associations (from GenCC):

intrinsic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
myopathy, congenital, with structured cores and z-line abnormalities
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy 1AA
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
myopathy, distal, 6, adult-onset, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 1-236720121-C-T is Benign according to our data. Variant chr1-236720121-C-T is described in ClinVar as [Benign]. Clinvar id is 43938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.102 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.378C>T	p.Asn126Asn	synonymous_variant	Exon 4 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.378C>T	p.Asn126Asn	synonymous_variant	Exon 4 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.553C>T		non_coding_transcript_exon_variant	Exon 4 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.378C>T	p.Asn126Asn	synonymous_variant	Exon 4 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.934

AC:

142084

AN:

152138

Hom.:

66832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.814

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.897

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

0.985

Gnomad SAS

AF:

0.970

Gnomad FIN

AF:

0.987

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.996

Gnomad OTH

AF:

0.948

GnomAD2 exomes

AF:

0.961

AC:

241683

AN:

251374

AF XY:

0.968

show subpopulations

Gnomad AFR exome

AF:

0.817

Gnomad AMR exome

AF:

0.871

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

0.980

Gnomad FIN exome

AF:

0.988

Gnomad NFE exome

AF:

0.995

Gnomad OTH exome

AF:

0.971

GnomAD4 exome

AF:

0.985

AC:

1437881

AN:

1459586

Hom.:

709267

Cov.:

AF XY:

0.986

AC XY:

715849

AN XY:

726288

show subpopulations

African (AFR)

AF:

0.808

AC:

27022

AN:

33426

American (AMR)

AF:

0.872

AC:

39014

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26116

AN:

26124

East Asian (EAS)

AF:

0.984

AC:

39030

AN:

39670

South Asian (SAS)

AF:

0.971

AC:

83728

AN:

86200

European-Finnish (FIN)

AF:

0.989

AC:

52835

AN:

53416

Middle Eastern (MID)

AF:

0.985

AC:

5675

AN:

5764

European-Non Finnish (NFE)

AF:

0.996

AC:

1105522

AN:

1109962

Other (OTH)

AF:

0.977

AC:

58939

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

1051

2102

3152

4203

5254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.934

AC:

142161

AN:

152256

Hom.:

66858

Cov.:

AF XY:

0.933

AC XY:

69421

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.814

AC:

33752

AN:

41488

American (AMR)

AF:

0.896

AC:

13708

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

0.985

AC:

5105

AN:

5184

South Asian (SAS)

AF:

0.970

AC:

4688

AN:

4834

European-Finnish (FIN)

AF:

0.987

AC:

10478

AN:

10618

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.996

AC:

67754

AN:

68048

Other (OTH)

AF:

0.949

AC:

2006

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

420

839

1259

1678

2098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.975

Hom.:

110216

Bravo

AF:

0.921

Asia WGS

AF:

0.963

AC:

3351

AN:

3478

EpiCase

AF:

0.996

EpiControl

AF:

0.995

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Myopathy, congenital, with structured cores and z-line abnormalities

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 11, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

1.6

(source)

DANN

Benign

0.67

PhyloP100

-0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs1341863

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over